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Sphingosine and FTY720 directly bind pro-survival 14-3-3 proteins to regulate their function
Joanna M Woodcock1, Yuefang Ma, Carl Coolen
1Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, SA 5000, Australia. Joanna.Woodcock@health.sa.gov.au
Cellular Signalling
|April 21, 2010
Summary
Sphingosine and 14-3-3 proteins directly interact to control cell death. Sphingosine binding to 14-3-3 proteins enables phosphorylation, inhibiting their survival signals and impacting cancer therapy.
Area of Science:
- Cell biology
- Molecular mechanisms of apoptosis
- Signal transduction
Background:
- The 14-3-3 protein family is known to protect cells from apoptosis by regulating pro-apoptotic molecules.
- Sphingosine, a cationic lipid, is associated with physiological apoptosis and can induce cell death through poorly understood mechanisms.
Purpose of the Study:
- To elucidate the interaction between sphingosine and 14-3-3 proteins in the regulation of cell death.
- To investigate the role of sphingosine kinase 1 in this pathway.
- To explore the therapeutic potential of sphingosine analogues like FTY720.
Main Methods:
- Investigated the direct interaction between sphingosine and 14-3-3 proteins.
- Assessed the effect of sphingosine binding on 14-3-3 protein phosphorylation.
- Utilized a non-phosphorylatable 14-3-3zeta mutant to study the biological significance of phosphorylation.
- Examined the role of sphingosine kinase 1 and the impact of FTY720.
Main Results:
- Sphingosine directly binds to 14-3-3 proteins, inducing phosphorylation at the dimer interface and abolishing pro-survival signaling.
- Sphingosine kinase 1 activity reduces sphingosine availability for 14-3-3 interaction, thereby inhibiting cell death.
- FTY720, a sphingosine analogue, potentiates 14-3-3 phosphorylation similarly to sphingosine.
- A non-phosphorylatable 14-3-3zeta mutant demonstrated reduced apoptosis induced by sphingosine and FTY720.
Conclusions:
- Direct association of sphingosine with 14-3-3 proteins is crucial for 14-3-3 phosphorylation, a key event in controlling cell fate.
- This sphingosine-14-3-3 axis offers new mechanistic insights into cell survival, oncogenesis, and the function of sphingosine kinase 1.
- FTY720 exhibits potential as an anti-cancer agent by targeting this newly identified mechanism.
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